Achieving Adequate Exposure for Effective Immunosuppression

Transcription

1 Pharmacokinetics of Tacrolimus Achieving Adequate Exposure for Effective Immunosuppression An Exploration of the Literature November 2017 Sponsored by:

2 2017 Veloxis Pharmaceuticals, Inc. ENV /17 ENVARSUS XR is a trademark of Veloxis Pharmaceuticals A/S. All other trademarks are property of their respective owners.

3 Pharmacokinetics of Tacrolimus Achieving Adequate Exposure for Effective Immunosuppression Background Since its introduction, tacrolimus has been the gold standard in immunosuppression and is used in more than 90% of new transplant patients. 1 It is more effective than cyclosporine at preventing rejection, and for that reason has become the most-commonly used calcineurin inhibitor The pharmacokinetics of tacrolimus are highly variable, with more pronounced differences noted in certain patient populations; furthermore, some patients are more sensitive to these differences in pharmacokinetics. Because of the unique characteristics of how tacrolimus is absorbed and metabolized, it is important to consider the pharmacokinetic profile of this drug and the formulation selected. There is significant risk of rejection posed by underexposure and, conversely, significant risk of adverse events and side effects when patients are exposed to high concentrations of tacrolimus. Pharmacology Overview Mechanism of Action Tacrolimus inhibits T-lymphocyte activation, although the exact mechanism of action is unknown. Experimental evidence suggest that tacrolimus enters T-cells and binds to an intracellular protein, FKBP-12. A complex of tacrolimus-fkbp-12, calcium, calmodulin, and calcineurin is then formed and the phosphatase activity of calcineurin inhibited. This effect may prevent the dephosphorylation (and therefore activation) and translocation of nuclear factor of activated T-cells (NFAT). The net result is the prevention on IL-2 production and inhibition of T- lymphocyte activation, i.e. immunosuppression. 5 ADME of Tacrolimus 5-6 Absorption Distribution Metabolism Excretion Incomplete and highly variable; oral bioavailability varies for the various formulations resulting in different dosing requirements. 5-7 Tacrolimus absorption is subject to diurnal variation. Plasma protein binding is ~99%, primarily bound to albumin and alpha-1 glycoprotein; high association with erthryocytes Significant pre-systemic metabolism via CYP3A found in highest concentrations in the proximal intestine 8 Biliary: 92.6 ± 30.7% Urinary: 2.3 ±1.1% Tacrolimus Pharmacokinetics Like most oral drugs, tacrolimus demonstrates a pharmacokinetic curve characterized by an initial peak and a gradual decline. There are a number of key clinical parameters to consider when evaluating the pharmacokinetic (PK) profile of tacrolimus. AUC (ng hr/ml) C min or C 0 (ng/ml) C max (ng/ml) T max (h) Area Under the Curve is a measure of total exposure to tacrolimus The trough or minimum whole blood concentration The peak or maximum whole blood concentration The time in hours from dose to peak; a shorter Tmax corresponds with a sharper spike in concentration 1

4 Fluctuation (%) Swing (%) The peak to trough change in concentration around the average concentration The peak to trough change in concentration relative to the minimum concentration Lower fluctuation and swing are indicative of a flatter PK profile and are generally desirable; it is hypothesized that flatter kinetics may improve the continuity of the drug s effect and by reducing high peak concentrations, avoid or reduce the severity of adverse events. 9 Narrow Therapeutic Window Tacrolimus is characterized by a Narrow Therapeutic Window (NTW) because the range of drug exposure between underimmunosuppression and overimmunosuppression is small. 10 Consequences of being outside NTW Adverse outcomes are associated with tacrolimus levels outside of the therapeutic range. Overimmunosuppression (high concentrations) may increase the risk of adverse events, whereas underimmunosuppression (low concentrations) may increase the risk of graft rejection. 11 Opportunistic infections 12 Nephrotoxicity12, 13 Neurotoxicity12, 13 Malignancy 12 New onset diabetes12, 13 Neurotoxic Peak Effects Patients are at greatest risk of neurotoxic side effects during the undesirable initial high peak concentration associated with immediate-release tacrolimus (IR-Tac). 14 These types of events, including tremor, mood alteration, reduced cognitive ability and headaches, may prompt a reduction in tacrolimus dosage that can potentially place patients at risk if it results in inadequate tacrolimus exposure. 15 Serious side effects may also prompt a patient to stop taking their tacrolimus as prescribed. 16 Therefore, it is advisable to see if the patient s regimen can be adjusted to minimize adverse events without resulting in underimmunosuppression. Variability in IR-Tacrolimus Exposure and Peak Concentration Due to the mechanism by which tacrolimus is absorbed and metabolized in the body, the same dose can produce significantly different levels of exposure in different patients. 17 In one study examining PK response after the first dose of tacrolimus, the concentration at 12 hours, C12, among the 18 patients was similar, with a range of ng/ml. The peak concentrations these patients Overimmunosuppression Underimmunosuppression Acute rejection 13 Chronic rejection 13 Clinical benefits of the differences in ENVARSUS XR pharmacokinetics have not been established. Please see Important Safety Information on page 8, including Boxed Warning, and accompanying Full Prescribing Information. Figure 1: Tacrolimus concentration of 18 patients after the first oral dose of IR-Tacrolimus. Adapted from Velckovic-Radovanovic. 17 2

5 were exposed to, however, had a range of about ng/ml (Figure 1). Although two patients may have had similar trough levels, these data demonstrate that their measured Cmax values can vary significantly. Additionally, the AUCs varied significantly, with a standard deviation of 25.7 ng hr/ml, or 32.5% of the mean AUC. This study is consistent with other published results and makes it clear that immunosuppression must be individualized to ensure both adequate exposure and a tolerable side effect profile. Pharmacokinetic Differences in Tacrolimus Formulations There are currently three formulations of oral tacrolimus available. Twice-daily Immediate Release Tacrolimus (IR-Tac), originally introduced as Prograf (tacrolimus) capsules in 1994, represented a monumental step forward in immunosuppression. Two once-daily formulations of tacrolimus are also now available: Astagraf XL (tacrolimus extendedrelease capsules) and ENVARSUS XR (tacrolimus extended-release) tablets. Astagraf XL is referred by different terms in literature including ER-Tac and TacXL; ENVARSUS XR is normally referred to as LCPTacro or LCPT. The three formulations display significant differences in pharmacokinetic profiles. The formulations are not interchangeable; the right drug should be deliberately selected for each patient. 7-5 In a robust, two-sequence, three-period randomized crossover study, the pharmacokinetics of the three formulations were compared in stable adult kidney transplant patients (N=31). 18 After randomization, each patient received IR-Tac followed by either ENVARSUS XR followed by ER-Tac or ER-Tac followed by ENVARSUS XR. Twenty-four-hour PK collections were performed at the end of each steady state 1-week period; a total of 17 or 21 time points were sampled over 24 hours. Because dose adjustments were not allowed during the study period, and fixed dosing conversion was used, different AUCs were observed. For this reason, it is useful to examine a pharmacokinetic curves normalized for exposure as shown in Figure 2. The observed exposure of IR-Tac was used to normalize exposure for ENVARSUS XR and ER-Tac as depicted in the figure. ENVARSUS XR showed lower Cmax and longer Tmax but no differences were seen for these parameters between ER-Tac and IR-Tac. Time (h) since morning dose Adapted from Tremblay et al. Figure 2: Exposure (AUC)-normalized mean whole blood concentrations of tacrolimus based on conversion factors of 1 IR-Tac:1.08 ER-Tac:0.70 ENVARSUS XR 3

6 Targeting Exposure Tacrolimus metabolism is highly variable between patients. Additionally, patients with different risk profiles and medication regimens may need different levels of immunosuppression. For these reasons, it is important to select the appropriate target, measure exposure, and adjust the dose of tacrolimus accordingly. Exposure vs Trough It is well-established that patients without adequate exposure are at higher risk of acute rejection, especially in the early transplant period. 19 Though there is significant research into biomarkers, there is not at present a practical means to measure the level of immunosuppression in a patient. Therefore, surrogate measures are used to assess tacrolimus exposure and to titrate doses. The two metrics commonly found in the literature are AUC and Cmin. AUC provides a better picture of exposure over time, but is more resource intensive to measure, requiring numerous blood draws over the test period. While there have been some models developed that allow the estimation of AUC using fewer samples, these still require multiple blood draws. 20 In practice, therapeutic drug monitoring of tacrolimus is accomplished by measuring Cmin. The relationship between Cmin and AUC is well studied and there is a strong linear correlation between the two parameters for all three oral tacrolimus formulations available. 21, 22 However, Cmin is not a perfect indicator of AUC and there can be considerable variation from patient to patient. 17 Clinical benefits of the differences in ENVARSUS XR pharmacokinetics have not been established. Please see Important Safety Information on page 8, including Boxed Warning, and accompanying Full Prescribing Information. Selecting a Target While there has been considerable research into the topic, there is not a universal standard target Cmin. Each individual patient s risk of rejection, evaluating such criteria as age and time post-transplant, must be considered to select an appropriate target. High Peak Not Associated With or Required for Efficacy Peak concentration, Cmax, is not correlated with efficacy outcomes. In multiple prospective trials, ENVARSUS XR demonstrated no difference in key outcomes, including death, BPAR, or graft loss while exposing patients to a significantly lower peak than IR-Tac. 23, 24 Genetic Factors and Rapid Metabolizers of Tacrolimus Genetic factors account for the majority of individual variation in tacrolimus absorption. 25 Who are Rapid Metabolizers? Rapid Metabolizers, sometimes called Fast Metabolizers, are expressors of the CYP3A5*1 allele, and have increased functional CYP3A5 enzyme activity, leading to profound metabolism of tacrolimus. Like most drugs, tacrolimus is primarily metabolized by the liver. Unlike many other drugs, however, tacrolimus undergoes significant presystemic metabolism in the small intestine. This metabolism is due to higher concentrations of CYP3A4/5 found in the proximal GI tract. 12, 25 Additionally, tacrolimus is a substrate for the efflux pump P-glycoprotein (P-gp). Genetic differences (polymorphisims) in the expression of CYP3A4/5 and P-gp can cause considerable interpatient variability in tacrolimus concentrations by impacting the rate and extent of absorption and, therefore, overall bioavailability of the drug. 25, 26 4

7 Prevalence and Identification of Rapid Metabolizers While the presence of the CYP3A5*1 allele is correlated with race and is most commonly found among black patients, race alone is not a sufficient clinical predictor. 29 As many as 30% of Caucasians are expressors, and about 1 in 3 kidney transplant recipients is a rapid metabolizer of tacrolimus. 27 Rapid metabolizers can be identified definitively by genotyping; however, genotyping is expensive and has not been shown to improve outcomes since dose can be adjusted based on therapeutic drug monitoring. 28 Rapid metabolizers can also be identified based on the dose of tacrolimus required; to achieve the same target trough as a non-expressor, patients require 1.5-2x higher doses of tacrolimus. 25, 29 The recent ASERTAA Study * classified patients by genotype and found that while non-expressors required an average daily IR-Tac dose of 6.27 mg/day, rapid metabolizers required mg/day on average. Additional pharmacokinetic parameters are reported in Table 1. Another metric to identify patients who may be rapid metabolizers is the Trough Concentration to Dose ratio, or C/D ratio. This value is obtained by dividing the Cmin or trough by the total daily dose. Lower C/D values, as a result of requiring a higher dose to achieve target trough, have been associated with worse outcomes. Patients with lower C/D values may require additional attention when designing an immunosuppression regimen. 30 Underimmunosuppression in Rapid Metabolizers Rapid metabolizers of tacrolimus are at risk of underimmunosuppression; in the DeKAF study, median trough levels in African-Americans were below target despite a 60% higher median dose of IR- Tac. 25 Peaks in Rapid Metabolizers and Tacrolimus Formulation Selection The mean pharmacokinetic responses found in the ASERTAA Study are reported in Figure 3. In the ASERTAA Study, rapid metabolizers required a 61% PK Parameter CYP3A5 Expressor (n=35) CYP3A5 Non-expressor (n=11) ENVARSUS XR IR-Tac ENVARSUS XR IR-Tac Total Daily Dose (mg/day) [1] Weight normalized TDD (mg/kg) AUC Cmax [2] Cmin Adapted from Trofe-Clarke et al 29 Abbreviations: AUC0-24=Area under the concentration-time curve from time 0 to 24 hours; Cmax= Maximum observed concentration, peak; Cmin= Minimum blood concentration observed over the 24-hour interval (0 24 hours) [1] p<0.02 for IR-Tac, non-expressor vs expressor [2] p=0.04 for IR-Tac, non-expressor vs expressor Table 1: ASERTAA Study Pharmacokinetic Results * A Study of Extended-Release Tacrolimus in African- Americans 5

8 Figure 3: (Top) Mean Tacrolimus Whole Blood Concentration for Rapid Metabolizers vs Nonexpressors on IR-Tac; (Bottom) Mean Tacrolimus Whole Blood Concentration for Rapid Metabolizers and Nonexpressors on ENVARSUS XR and IR-Tac. Adapted from Trofe-Clarke, et al. 29 higher dose of IR-Tac to achieve the target trough. While this higher dose raised the target trough to the same level as non-expressors, it also resulted in an increase in the peak concentration, with a 34% higher average Cmax in rapid metabolizers than in nonexpressors. 29 Interestingly, after conversion to ENVARSUS XR, there were no statistical differences in the peaks experienced by rapid metabolizers and non-expressors. Adherence and Exposure Patient adherence to therapy is crucial to achieving the targeted exposure within the narrow therapeutic window. 31 Despite its importance, non-adherence continues to be a significant problem among kidney transplant patients, especially as they get further out from their transplant. 32 Missing even a single dose of tacrolimus can result in the patient being below the target level of exposure for a period extending beyond just the next dose. 33 Side Effects and Adherence Because adherence is essential to adequate and consistent exposure, and because tacrolimus side effects can be influenced by pharmacokinetic factors, it is worth considering adherence and pharmacokinetics in tandem. Severe side effects are a major predictor of poor adherence to a medication regimen. 16 In particular, the patient s perceived severity of side effects, subjective evaluation of the impairment by the side effects and the duration of 6

9 those side effects are all significant predictors of nonadherence. Dosing to Support Consistent Exposure Patients on twice-daily medication regimens are more likely to miss their evening dose than their morning dose. 34 Medication complexity has been identified as a risk factor for non-adherence; the KDIGO guidelines recommend dosing medications once daily where possible, and no more than twice daily. 35, 36 In patients where there is difficulty achieving target trough, switching the patient to TID dosing may not be ideal due to potential non-adherence, especially among patients with mental impairment. 35, 37 None of the available tacrolimus formulations have been evaluated for safety and efficacy in Phase III trials with TID dosing. Evaluating the patient s whole medication regimen may be in order as an alternative to implementing a TID dosing regimen. Missed Doses with Once- vs Twice-Daily Tacrolimus Unlike IR-Tac, patients taking once-daily formulations of tacrolimus can take their normal total daily dose later in the day if they miss a dose. 5, 7 For example, a patient taking ENVARSUS XR can take their normal dose up to 15 hours after a missed dose and receive their entire daily dose of tacrolimus. Other Pharmacokinetic Considerations Food Effects There are numerous external factors that can impact tacrolimus exposure. Taking tacrolimus with food will result in significantly reduced absorption; the effect is particularly great if tacrolimus is consumed with a high fat meal. All patients on tacrolimus should be educated about the impact of substances like alcohol and grapefruit juice on tacrolimus. Diurnal Variation Tacrolimus demonstrates significant diurnal variability, with the AUC and peak much higher in the morning than in the evening. 38 Because of this, the once-daily formulations must be taken at the same time each day to ensure consistent exposure. 7, 5 Conclusion It is established that exposure is closely linked to calcineurin inhibitor effectiveness. Because the pharmacokinetics of tacrolimus can vary so widely from one patient to the next, therapeutic drug monitoring has long been standard practice. As part of the routine evaluation of patients on immunosuppression, it is important to ask about side effects and medication adherence. Patient responses, along with information from therapeutic drug monitoring, may help identify when there is a problem that may point to over or underexposure that may lead to suboptimal immunosuppression. One important consideration is to individualize the immunosuppression regimen for each patient. To that end, it may be worth systematically evaluating the immunosuppression regimen of patients who are unable to maintain adequate immunosuppression, requiring particularly high doses of IR-Tac, or experiencing undesirable side effects. Finally, the three formulations of oral tacrolimus available in the United States (IR-Tac, Astagraf XL or ER-Tac, and ENVARSUS XR or LCPT) are different in their bioavailability and are therefore not bioequivalent. None of the formulations are interchangeable or substitutable, so it is important that clinicians assess and ensure that each patient receives the product that they feel is best suited for that particular patient's needs. Clinical benefits of the differences in ENVARSUS XR pharmacokinetics or potential differences in adherence have not been established. Please see Important Safety Information on page 8, including Boxed Warning, and accompanying Full Prescribing Information. 7

10 Clinical benefit of the differences in ENVARSUS XR pharmacokinetics or potential differences in adherence have not been established. INDICATIONS AND USAGE ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants. Limitation of Use: ENVARSUS XR extended-release tablets are not interchangeable or substitutable with other tacrolimus products. IMPORTANT SAFETY INFORMATION WARNING: MALIGNANCIES AND SERIOUS INFECTIONS Increased risk for developing serious infections and malignancies with ENVARSUS XR or other immunosuppressants that may lead to hospitalization or death. CONTRAINDICATIONS ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus. WARNINGS AND PRECAUTIONS Lymphoma and Other Malignancies: Immunosuppressants, including ENVARSUS XR, increase the risk of developing lymphomas and other malignancies, particularly of the skin. Posttransplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. Serious Infections: Immunosuppressants, including ENVARSUS XR, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Graft Rejection and Other Serious Adverse Reactions due to Medication Errors: Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to underor over-exposure to tacrolimus. ENVARSUS XR is not interchangeable or substitutable with tacrolimus immediate-release products or other tacrolimus extended-release products. New Onset Diabetes After Transplant: ENVARSUS XR caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Nephrotoxicity: ENVARSUS XR, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. The risk for nephrotoxicity may increase when ENVARSUS XR is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity. Neurotoxicity: ENVARSUS XR may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions. Hyperkalemia: Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ENVARSUS XR. Concomitant use of agents associated with hyperkalemia may increase the risk for hyperkalemia. Hypertension: Hypertension is a common adverse reaction of ENVARSUS XR therapy and may require antihypertensive therapy. Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A Inhibitors: The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions. Therefore, adjust ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations when coadministering ENVARSUS XR with strong CYP3A inhibitors or strong CYP3A inducers. QT Prolongation: ENVARSUS XR may prolong the QT/QTc interval and cause Torsade de Pointes. Avoid ENVARSUS XR in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances. When coadministering ENVARSUS XR with other substrates and/or inhibitors of CYP3A, a reduction in ENVARSUS XR dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended. Immunizations: Whenever possible, administer the complete complement of vaccines before transplantation and treatment with ENVARSUS XR. Avoid the use of live attenuated vaccines during treatment with ENVARSUS XR. Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with ENVARSUS XR. Pure Red Cell Aplasia: Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. If PRCA is diagnosed, consider discontinuation of ENVARSUS XR. ADVERSE REACTIONS Most common adverse reactions (incidence 10%) reported with ENVARSUS XR include: diarrhea and blood creatinine increased. USE IN SPECIFIC POPULATIONS Pregnancy: Based on animal data may cause fetal harm. Use only if the potential benefit justifies the risk. Nursing Mothers: Tacrolimus is present in human milk. Discontinue drug or nursing, taking into account the importance of drug to the mother. Pediatric Use: The safety and efficacy of ENVARSUS XR in pediatric patients have not been established. Geriatric Use: Clinical studies of ENVARSUS XR did not include sufficient numbers of patients aged 65 and over to determine whether they respond differently from younger patients. Renal Impairment: Frequent monitoring of renal function is recommended. Lower doses may be required. Hepatic Impairment: Frequent monitoring of tacrolimus trough concentrations is recommended. With greater tacrolimus whole blood trough concentrations in patients with severe hepatic impairment, there is a greater risk of adverse reactions and dosage reduction is recommended. Race: African-American patients may require higher doses to attain comparable trough concentrations compared to Caucasian patients. To report SUSPECTED ADVERSE REACTIONS, contact Veloxis Pharmaceuticals, Inc. at VELOXIS ( ) or FDA at FDA-1088 or visit Please see accompanying full Prescribing Information, including Boxed Warning. 8

11 References 1 Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2015 Annual Data Report: Kidney. Organ Procurement and Transplantation Network (OPTN) and Scientific Registry of Transplant Recipients (SRTR). Am J Transplant. 2017;17 (Suppl 1): The U.S. Multicenter FK506 Liver Study Group. A comparison of tacrolimus (FK 506) and cyclosporine for immunosuppression in liver transplantation. N Engl J Med. 1994;331: Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation. N Engl J Med. 2007;357: Solez K, Vincenti F and Filo R for the FK506 Kidney Transplant Study Group. A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. Transplantation. 1998;66(12): ENVARSUS XR (tacrolimus extended-release tablets). Veloxis Pharmaceuticals. Cary, NC. April Prograf (tacrolimus) capsules. Astellas Pharma. Northbrook, IL Astagraf XL (tacrolimus extended-release). Astellas Pharma. Northbrook, IL Thörn M, Finnström N, Lundgren S, Rane A, Lööf L. Cytochromes P450 and MDR1 mrna expression along the human gastrointestinal tract. Br J Clin Pharmacol. 2005;60(1): EMEA. Note for Guidance on Modified Release Oral and Transdermal Dosage Forms: Section II (Pharmacokinetic and Clinical Evaluation). London: European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products; Johnston A. Equivalence and interchangeability of narrow therapeutic index drugs in organ transplantation. Eur J Hosp Pharm Sci Pract. 2013;20(5): Endrenyi L, Tothfalusi L. Metrics for the evaluation of bioequivalence of modified-release formulations. AAPS J. 2012;14(4): Staatz CE, Tett SE. Clinical pharmacokinetics and pharmacodynamics of tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2004;43(10): Hesselink DA, Bouamar R, et al. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin Pharmacokinet. 2014;53(2): Eidelman BH, Abu-Elmagd K, Wilson J, et al. Neurologic complications of FK 506. Transplant Proc. 1991;23(6): Langone A, Steinberg SM, Gedaly R, et al; STRATO investigators. Switching study of kidney transplant patients with tremor to LCP-tacro (STRATO): an openlabel, multicenter, prospective phase 3b study. Clin Transplant. 2015;29(9): Reber S, Morawa E, et al. Prevalence and Modifiable Determinants of Non-Adherence in Adult Kidney Transplant Recipients in a German Sample. Z Psychosom Med Psychother 62/2016, Velickovic-Radovanovic RM, Paunovic G, Mikov M, et al. Clinical pharmacokinetics of tacrolimus after the first oral administration in renal transplant recipients. Basic Clin Pharmacol Toxicol. 2010; 106(6): Tremblay S, Nigro V, Weinberg J, et al. A Steady-State Head-to-Head Pharmacokinetic Comparison of All FK-506 (Tacrolimus) Formulations (ASTCOFF). Am J Transplant. 2017;17(2): Undre NA, van Hooff J, Christiaans M. Low Systemic Exposure to Tacrolimus Correlates With Acute Rejection. Transplantation Proceedings, 31, (1999) 20 Woillard, JB., Debord, J., Monchaud, C. et al. Population Pharmacokinetics and Bayesian Estimators for Refined Dose Adjustment of a New Tacrolimus Formulation in Kidney and Liver Transplant Patients. Clin Pharmacokinet (2017). 21 Hardingera KL, Park J, Schnitzler MA, et al. Pharmacokinetics of Tacrolimus in Kidney Transplant Recipients: Twice Daily Versus Once Daily Dosing American Journal of Transplantation 2004; 4:

12 22 Wlodarczyk Z, Squifflet JP, et al. Pharmacokinetics for Once- Versus Twice-Daily Tacrolimus Formulations in De Novo Kidney Transplantation: A Randomized, Open- Label Trial. American Journal of Transplantation. 2009; 9: Gaber AO, Alloway RR, Bodziak K, Kaplan B, Bunnapradist S. Conversion from twice-daily tacrolimus capsules to once-daily extended-release tacrolimus (LCPT): a phase 2 trial of stable renal transplant recipients. Transplantation. 2013;96(2): Bunnapradist S, Ciechanowski K, West-Thielke P, et al; MELT investigators. Conversion from twice-daily tacrolimus to once-daily extended release tacrolimus (LCPT). Am J Transplant. 2013;13(3): Jacobson PA, Oetting WS, Brearley AM, et al; for DeKAF Investigators. Novel polymorphisms associated with tacrolimus trough concentrations: results from a multicenter kidney transplant consortium. Transplantation. 2011;91(3): Haufroid V, Mourad M, Van Kerckhove V, et al. The effect of CYP3A5 and MDR1 (ABCB1`) polymorphisms on the pharmacokinetics of calcineurin inhibitors. Am J Health Syst Pharm. 2006;63(23): Kuehl P, Zhang J, Lin Y, et al. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet. 2001;27(4): Tremblay S and Alloway R. Clinical Evaluation of Modified Release and Immediate Release Tacrolimus Formulations. AAPS Journ. 2017: doi: /s z. [Epub ahead of print] 32 Dew MA, DiMartini AF, De Vito Dabbs A, et al. Rates and risk factors for nonadherence to the medical regimen after adult solid organ transplantation.transplantation. 2007;83(7): Saint-Marcoux F, Woillard J, et al. How To Handle a Missed or Delayed Dose Intake? A Pharmacokinetic Study Investigation. Pharmacological Research. 100 (2015) Kuypers DRJ, Peeters PC, Sennesael JJ, et al. Improved adherence to tacrolimus once-daily formulation in renal recipients: a randomized controlled trial using electronic monitoring. Transplantation. 2013; 95: Osterberg L and Blaschke T. Adherence to Medication. NEJM. 2005;353(5): KDIGO. Am J Transplantation. 2009;9 (Suppl 3):S1-S Hinkin C, et al. Medication Adherence among HIV+ adults. Neurology. 2002;59(12): Satoh S, Tada H, Tachiki Y, et al. Chrono and clinical pharmacokinetic study of tacrolimus in continuous intravenous administration. International Journal of Urology (2001) 8, Rancic N, Dragojevic-Simic V, et al. (2016) Economic Evaluation of Pharmacogenetic Tests in Patients Subjected to Renal Transplantation: A Review of Literature. Front. Public Health 4: Trofe-Clark J, Brennan DC, West-Thielke P, et al. Results of ASERTAA, a Randomized Prospective Crossover Pharmacogenetic Study of Immediate-Release Versus Extended-Release Tacrolimus in African American Kidney Transplant Recipients. Am J Kidney Dis. epub ahead of print. Published online November 20, Thölking G, Fortmann C, Koch R, et al. The Tacrolimus Metabolism Rate Influences Renal Function after Kidney Transplantation. Bueno V, ed. PLoS ONE. 2014;9(10):e doi: /journal.pone

13 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use ENVARSUS XR safely and effectively. See full prescribing information for ENVARSUS XR. ENVARSUS XR (tacrolimus extended-release tablets), for oral use Initial U.S. Approval: 1994 WARNING: MALIGNANCIES AND SERIOUS INFECTIONS See full prescribing information for complete boxed warning. Increased risk for developing serious infections and malignancies with ENVARSUS XR or other immunosuppressants that may lead to hospitalization or death (5.1, 5.2) INDICATIONS AND USAGE ENVARSUS XR is a calcineurin-inhibitor immunosuppressant indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations in combination with other immunosuppressants (1) Limitation of use: Not interchangeable or substitutable with other tacrolimus products (1, 5.3) DOSAGE AND ADMINISTRATION Take once daily on empty stomach, preferably in the morning (2.1) Avoid eating grapefruit or drinking grapefruit juice or alcohol (2.1) Recommended ENVARSUS XR starting doses (patients with severe hepatic impairment may require a lower starting dose) (2.2) Conversion from tacrolimus immediate-release products Administer 80% of the pre-conversion daily dose of tacrolimus immediate-release (2.3) ENVARSUS XR Target Whole Blood Trough Concentrations (2.2) 4 to 11 ng/ml African-Americans may need to be titrated to higher dosages to achieve the target tacrolimus concentrations (2.1) Assess tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any dosage change, after a change in co-administration of CYP3A inducers and/or inhibitors, or after a change in renal or hepatic function (2.3) DOSAGE FORMS AND STRENGTHS Extendedrelease tablets: 0.75 mg, 1 mg, 4 mg (3) CONTRAINDICATIONS Known hypersensitivity to tacrolimus (4) WARNINGS AND PRECAUTIONS G raft-rejection and other serious adverse reactions due to medication errors: Instruct patients or caregivers to recognize appearance of ENVARSUS XR tablets (5.3) New onset diabetes after transplant: Monitor blood glucose (5.4) N ephrotoxicity (acute and/or chronic) due to ENVARSUS XR or concomitant nephrotoxic drugs: Monitor renal function; consider dosage reduction (5.5) Neurotoxicity [including risk of posterior reversible encephalopathy syndrome (PRES)]: Monitor for neurologic abnormalities; reduce dosage or discontinue ENVARSUS XR (5.6) Hyperkalemia: Risk may be increased with other agents associated with hyperkalemia; monitor serum potassium levels (5.7) Hypertension: May require antihypertensive therapy (5.8) Q T prolongation: Consider obtaining electrocardiograms and monitoring electrolytes in patients at high risk (5.10) Pure red cell aplasia: Consider discontinuation (5.12) ADVERSE REACTIONS Most common adverse reactions (incidence 10%) include: diarrhea and blood creatinine increased (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Veloxis Pharmaceuticals, Inc. at VELOXIS ( ) or FDA at FDA-1088 or DRUG INTERACTIONS Risk of rejection with strong CYP3A inducers and risk of serious adverse reactions with strong CYP3A inhibitors: Adjust dose and monitor tacrolimus concentrations (2.1, 5.9, 7.2) See Full Prescribing Information for clinically significant drug interactions (7.1, 7.2) See 17 for PATIENT COUNSELING INFORMATION and Medication Guide. Revised: 4/2017 FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: MALIGNANCIES AND SERIOUS INFECTIONS 1 INDICATIONS AND USAGE 2 DOSAGE AND ADMINISTRATION 2.1 Administration Instructions 2.2 Conversion from Tacrolimus Immediate-Release Formulations 2.3 Therapeutic Drug Monitoring 3 DOSAGE FORMS AND STRENGTHS 4 CONTRAINDICATIONS 5 WARNINGS AND PRECAUTIONS 5.1 Lymphoma and Other Malignancies 5.2 Serious Infections 5.3 Graft Rejection and Other Serious Adverse Reactions due to Medication Errors 5.4 New Onset Diabetes After Transplant 5.5 Nephrotoxicity due to ENVARSUS XR and Drug Interactions 5.6 Neurotoxicity 5.7 Hyperkalemia 5.8 Hypertension 5.9 Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A Inhibitors 5.10 QT Prolongation 5.11 Immunizations 5.12 Pure Red Cell Aplasia 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience 6.2 Postmarketing Experience 7 DRUG INTERACTIONS 7.1 Mycophenolic Acid 7.2 Effects of Other Drugs/Substances on ENVARSUS XR 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Renal Impairment 8.7 Hepatic Impairment 8.8 Race 10 OVERDOSAGE 11 DESCRIPTION 12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacokinetics 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14 CLINICAL STUDIES 16 HOW SUPPLIED/STORAGE AND HANDLING 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed. FULL PRESCRIBING INFORMATION WARNING: MALIGNANCIES AND SERIOUS INFECTIONS Increased risk for developing serious infections and malignancies with ENVARSUS XR or other immunosuppressants that may lead to hospitalization or death [see Warnings and Precautions (5.1 and 5.2)] 1 INDICATIONS AND USAGE ENVARSUS XR is indicated for the prophylaxis of organ rejection in kidney transplant patients converted from tacrolimus immediate-release formulations, in combination with other immunosuppressants. Limitation of Use ENVARSUS XR extended-release tablets are not interchangeable or substitutable with other tacrolimus extended-release or immediate-release products [see Warnings and Precautions (5.3)]. 2 DOSAGE AND ADMINISTRATION 2.1 Administration Instructions Take ENVARSUS XR on an empty stomach at the same time of the day, preferably in the morning (to ensure consistent and maximum possible drug exposure) [see Clinical Pharmacology (12.2)]. Swallow ENVARSUS XR whole with fluid (preferably water); do not chew, divide, or crush the tablets. If a dose is missed, take it as soon as possible within 15 hours after missing the dose; beyond the 15-hour time frame, wait until the usual scheduled time to take the next regular daily dose. Do not double the next dose. Avoid eating grapefruit or drinking grapefruit juice or alcoholic beverage while taking ENVARSUS XR [see Drug Interactions (7.2)]. African-American patients, compared to Caucasian patients, may need to be titrated to higher ENVARSUS XR dosages to attain comparable trough concentrations [see Use in Specific Populations (8.8) and Clinical Pharmacology (12.2)]. 2.2 Conversion from Tacrolimus Immediate-Release Formulations To convert from a tacrolimus immediate-release product to ENVARSUS XR, administer an ENVARSUS XR once daily dose that is 80% of the total daily dose of the tacrolimus immediate-release product. Monitor tacrolimus whole blood trough concentrations and titrate ENVARSUS XR dosage to achieve target whole blood trough concentration ranges of 4 to 11 ng/ml. 2.3 Therapeutic Drug Monitoring Measure tacrolimus whole blood trough concentrations at least two times on separate days during the first week after initiation of dosing and after any change in dosage, after a change in co-administration of CYP3A inducers and/or inhibitors, or after a change in renal or hepatic function. When interpreting measured concentrations, consider that the time to achieve tacrolimus steady state is approximately 7 days after initiating or changing the ENVARSUS XR dose. Monitor tacrolimus whole blood trough concentrations using a validated assay [e.g., immunoassays or highperformance liquid chromatography with tandem mass spectrometric detection (HPLC/MS/MS)]. The immunosuppressive activity of tacrolimus is mainly due to the parent drug rather than to its metabolites. Immunoassays may react with metabolites as well as the parent drug. Therefore, whole blood tacrolimus trough concentrations obtained with immunoassays may be numerically higher than concentrations obtained with an assay using HPLC/MS/MS. Comparison of the whole blood tacrolimus trough concentrations of patients to those described in the prescribing information and other published literature must be made with knowledge of the assay method(s) employed. 3 DOSAGE FORMS AND STRENGTHS Oval, white to off-white uncoated extended-release tablets debossed with TCS on one side: 0.75 mg extended-release tablet: debossed with 0.75 on the other side. 1 mg extended-release tablet: debossed with 1 on the other side. 4 mg extended-release tablet: debossed with 4 on the other side. 4 CONTRAINDICATIONS ENVARSUS XR is contraindicated in patients with known hypersensitivity to tacrolimus. 5 WARNINGS AND PRECAUTIONS 5.1 Lymphoma and Other Malignancies Immunosuppressants, including ENVARSUS XR, increase the risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. Examine patients for skin changes and advise to avoid or limit exposure to sunlight and UV light. Post-transplant lymphoproliferative disorder (PTLD), associated with Epstein-Barr Virus (EBV), has been reported in immunosuppressed organ transplant patients. The risk of PTLD appears greatest in those individuals who are EBV seronegative. Monitor EBV serology during treatment. 5.2 Serious Infections Immunosuppressants, including ENVARSUS XR, increase the risk of developing bacterial, viral, fungal, and protozoal infections, including opportunistic infections. These infections may lead to serious, including fatal, outcomes. Serious viral infections reported include: Polyomavirus-associated nephropathy (especially due to BK virus infection), JC virus-associated progressive multifocal leukoencephalopathy (PML), and Cytomegalovirus (CMV) infections: CMV seronegative transplant patients who receive an organ from a CMV seropositive donor are at highest risk of CMV viremia and CMV disease. Monitor for the development of infection and adjust the immunosuppressive regimen to balance the risk of rejection with the risk of infection [see Adverse Reactions (6.1)]. 5.3 Graft Rejection and Other Serious Adverse Reactions due to Medication Errors Medication errors, including substitution and dispensing errors, between tacrolimus immediate-release products and tacrolimus extended-release products were reported outside the U.S. This led to serious adverse reactions, including graft rejection, or other adverse reactions due to under- or over-exposure to tacrolimus. ENVARSUS XR is not interchangeable or substitutable with tacrolimus immediate-release products or other tacrolimus extended-release products. Instruct patients and caregivers to recognize the appearance of ENVARSUS XR tablet [see Dosage Forms and Strengths (3)]. 5.4 New Onset Diabetes After Transplant ENVARSUS XR caused new onset diabetes after transplant (NODAT) in kidney transplant patients, which may be reversible in some patients. African-American and Hispanic kidney transplant patients are at an increased risk. Monitor blood glucose concentrations and treat appropriately [see Adverse Reactions (6.1) and Use in Specific Populations (8.8)]. 5.5 Nephrotoxicity due to ENVARSUS XR and Drug Interactions ENVARSUS XR, like other calcineurin-inhibitors, can cause acute or chronic nephrotoxicity. Consider dosage reduction in patients with elevated serum creatinine and tacrolimus whole blood trough concentrations greater than the recommended range. The risk for nephrotoxicity may increase when ENVARSUS XR is concomitantly administered with CYP3A inhibitors (by increasing tacrolimus whole blood concentrations) or drugs associated with nephrotoxicity (e.g., aminoglycosides, ganciclovir, amphotericin B, cisplatin, nucleotide reverse transcriptase inhibitors, protease inhibitors) [see Drug Interactions (7.2)]. Monitor renal function and consider dosage reduction if nephrotoxicity occurs. 5.6 Neurotoxicity ENVARSUS XR may cause a spectrum of neurotoxicities. The most severe neurotoxicities include posterior reversible encephalopathy syndrome (PRES), delirium, seizure, and coma; others include tremors, paresthesias, headache, mental status changes, and changes in motor and sensory functions [see Adverse Reactions (6.1 and 6.2)]. As symptoms may be associated with tacrolimus whole blood trough concentrations at or above the recommended range, monitor for neurologic symptoms and consider dosage reduction or discontinuation of ENVARSUS XR if neurotoxicity occurs. 5.7 Hyperkalemia Mild to severe hyperkalemia, which may require treatment, has been reported with tacrolimus including ENVARSUS XR. Concomitant use of agents associated with hyperkalemia (e.g., potassium-sparing diuretics, ACE inhibitors, angiotensin receptor blockers) may increase the risk for hyperkalemia [see Adverse Reactions (6.1)]. Monitor serum potassium levels periodically during treatment. 5.8 Hypertension Hypertension is a common adverse reaction of ENVARSUS XR therapy and may require antihypertensive therapy [see Adverse Reactions (6.1)]. Some antihypertensive drugs can increase the risk for hyperkalemia [see Warnings and Precautions (5.7)]. Calcium-channel blocking agents may increase tacrolimus blood concentrations and require dosage reduction of ENVARSUS XR [see Drug Interactions (7.2)]. 5.9 Risk of Rejection with Strong CYP3A Inducers and Risk of Serious Adverse Reactions with Strong CYP3A Inhibitors The concomitant use of strong CYP3A inducers may increase the metabolism of tacrolimus, leading to lower whole blood trough concentrations and greater risk of rejection. In contrast, the concomitant use of strong CYP3A inhibitors may decrease the metabolism of tacrolimus, leading to higher whole blood trough concentrations and greater risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6 and 5.10)]. Therefore, adjust ENVARSUS XR dose and monitor tacrolimus whole blood trough concentrations when coadministering ENVARSUS XR with strong CYP3A inhibitors (e.g., telaprevir, boceprevir, ritonavir, ketoconazole, itraconazole, voriconazole, clarithromycin) or strong CYP3A inducers (e.g., rifampin, rifabutin) [see Dosage and Administration (2.3) and Drug Interactions (7.2)] QT Prolongation ENVARSUS XR may prolong the QT/QTc interval and cause Torsade de Pointes. Avoid ENVARSUS XR in patients with congenital long QT syndrome. Consider obtaining electrocardiograms and monitoring electrolytes (magnesium, potassium, calcium) periodically during treatment in patients with congestive heart failure, bradyarrhythmias, those taking certain antiarrhythmic medications or other products that lead to QT prolongation, and those with electrolyte disturbances (e.g., hypokalemia, hypocalcemia, or hypomagnesemia). When coadministering ENVARSUS XR with other substrates and/or inhibitors of CYP3A, a reduction in ENVARSUS XR dosage, monitoring of tacrolimus whole blood concentrations, and monitoring for QT prolongation is recommended [see Drug Interactions (7.2)] Immunizations Whenever possible, administer the complete complement of vaccines before transplantation and treatment with ENVARSUS XR. Avoid the use of live attenuated vaccines during treatment with ENVARSUS XR (e.g., intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines). Inactivated vaccines noted to be safe for administration after transplantation may not be sufficiently immunogenic during treatment with ENVARSUS XR Pure Red Cell Aplasia Cases of pure red cell aplasia (PRCA) have been reported in patients treated with tacrolimus. All of these patients reported risk factors for PRCA such as parvovirus B19 infection, underlying disease, or concomitant medications associated with PRCA. A mechanism for tacrolimus-induced PRCA has not been elucidated. If PRCA is diagnosed, consider discontinuation of ENVARSUS XR. 6 ADVERSE REACTIONS 6.1 Clinical Studies Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. In addition, the clinical studies were not designed to establish comparative differences across study arms with regards to the adverse reactions discussed below. In an open label, randomized, multinational conversion study, stable kidney transplant patients on a tacrolimus immediate-release product and concomitant immunosuppressants were randomized to treatment with ENVARSUS XR (N=162) or to continued treatment on the tacrolimus immediate-release product (N=162) and treated for a duration of 12 months [see Clinical Studies (14)]. The proportion of patients who discontinued treatment due to adverse reactions was 7.4% and 1.2% in the ENVARSUS XR and tacrolimus immediate-release treatment groups, respectively, through 12 months of treatment. The most common adverse reactions leading to discontinuation of study drug in the ENVARSUS XR treatment group was cardiac arrest (2 events). Infections The overall incidence of infections, serious infections, and infections with identified etiology reported in stable kidney transplant recipients treated with ENVARSUS XR or tacrolimus immediate-release product are shown in Table 1. Table 1. Percentage of Stable Patients with Infections Through One Year Post- Treatment in the Conversion Study a ENVARSUS XR ± steroids, MMF/MPS or AZA N=162 Tacrolimus immediate-release product ± steroids, MMF/MPS or AZA N=162 All infections 46% 48% Respiratory Infections 26% 28% Urinary Tract Infections 10% 14% Bacterial Infections 7% 5% Fungal Infections 4% 4% Gastrointestinal Infections 4% 5% BK virus b 2% 2% Cytomegalovirus Infections 2% 1% Serious Infections 8% 9% a The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus immediate-release product for the adverse reactions reported in this table. b BK virus associated nephropathy (BKVAN) occurred in 1.2% (2/162) and 0.6% (1/162) in the ENVARSUS XR and tacrolimus immediate-release treatment groups, respectively. New Onset Diabetes After Transplantation (NODAT) New onset diabetes after transplantation (NODAT) was defined by the composite occurrence of fasting plasma glucose values 126 mg/dl, 2-hour postprandial plasma glucose of at least 200 mg/dl (in oral glucose tolerance test) on 2 or more consecutive occasions post baseline, insulin requirement for 31 days, an oral hypoglycemic agent use 31 days, or HbA 1c 6.5% (at least 3 months after randomization) among kidney transplant patients with no medical history of diabetes. The incidence of NODAT for the stable kidney transplant study through one year post-transplant is summarized in Table 2 below [see Warnings and Precautions (5.4)]. Table 2. Percentage of Stable Patients with NODAT Through 1 Year Post- Treatment in the Conversion Study a ENVARSUS XR ± steroids, MMF/MPS or AZA (N=90) Tacrolimus immediate-release product ± steroids, MMF/MPS or AZA (N=95) Composite NODAT b 10% 11% HbA 1c 6.5% 3% 7% Fasting Plasma Glucose Values 126 mg/dl on 2 consecutive occurrences 8% 6% Oral hypoglycemic use 1% 1% Insulin Use 31 days 1% 0% a The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus immediate-release product for the adverse reactions reported in this table. b Analyses restricted to patients at risk for NODAT Common Adverse Reactions The incidence of adverse reactions that occurred in 5% of ENVARSUS XR-treated patients compared to tacrolimus immediate-release product through one year of treatment in the conversion study is shown by treatment group in Table 3. Adverse Reaction Table 3. Adverse Reactions ( 5%) in Stable Kidney Transplant Patients Through 1 Year Post- Treatment in the Conversion Study a ENVARSUS XR N=162 Tacrolimus immediate-release product N=162 Diarrhea 14% 9% Blood Creatinine Increased 12% 9% Urinary Tract Infection 9% 14% Nasopharyngitis 9% 11% Headache 9% 7% Upper Respiratory Tract Infection 7% 9% Peripheral Edema 7% 6% Hypertension 4% 6% a The stable kidney transplant study was not designed to support comparative claims of ENVARSUS XR compared to tacrolimus immediate-release for the adverse reactions reported in this table. 6.2 Postmarketing Experience The following adverse reactions have been reported from marketing experience with tacrolimus in the U.S. and outside the U.S. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Blood and Lymphatic System Disorders: Agranulocytosis, decreased blood fibrinogen, disseminated intravascular coagulation, hemolytic anemia, hemolytic uremic syndrome, pancytopenia, prolonged activated partial thromboplastin time, pure red cell aplasia [see Warnings and Precautions (5.12)], thrombocytopenic purpura, thrombotic thrombocytopenic purpura Cardiac Disorders: Atrial fibrillation, atrial flutter, cardiac arrhythmia, cardiac arrest, electrocardiogram T wave abnormal, flushing, myocardial hypertrophy, myocardial infarction, myocardial ischaemia, pericardial effusion, QT prolongation, supraventricular extrasystoles, supraventricular tachycardia, Torsade de Pointes, deep limb venous thrombosis, ventricular fibrillation Ear Disorders: Hearing loss including deafness Eye Disorders: Blindness, photophobia, optic atrophy Gastrointestinal Disorders: Colitis, dysphagia, gastrointestinal perforation, impaired gastric emptying, intestinal obstruction, mouth ulceration, peritonitis, stomach ulcer Hepatobiliary Disorders: Bile duct stenosis, cholangitis, cirrhosis, fatty liver, hepatic cytolysis, hepatic failure, hepatic necrosis, hepatic steatosis, jaundice, hemorrhagic pancreatitis, necrotizing pancreatitis, venoocclusive liver disease Hypersensitivity Reactions: Hypersensitivity, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria Immune System Disorders: Graft versus host disease (acute and chronic) Metabolism and Nutrition Disorders: Glycosuria, increased amylase, pancreatitis Musculoskeletal and Connective Tissue Disorders: Myalgia, polyarthritis, rhabdomyolysis Neoplasms: Lymphoma including EBV-associated lymphoproliferative disorder, PTLD [see Warnings and Precautions (5.1)]; leukemia Nervous System Disorders: Carpal tunnel syndrome, cerebral infarction, coma, dysarthria, flaccid paralysis, hemiparesis, mental disorder, mutism, nerve compression, posterior reversible encephalopathy syndrome (PRES) [see Warnings and Precautions (5.6)], progressive multifocal leukoencephalopathy (PML) sometimes fatal [see Warnings and Precautions (5.2)], quadriplegia, speech disorder, status epilepticus, syncope Renal and Urinary Disorder: Acute renal failure, hemorrhagic cystitis, hemolytic uremic syndrome, micturition disorder Respiratory, Thoracic and Mediastinal Disorders: Acute respiratory distress syndrome, interstitial lung disease, lung infiltration, pulmonary hypertension, respiratory distress, respiratory failure Skin and Subcutaneous Tissue Disorders: Hyperpigmentation, photosensitivity 7 DRUG INTERACTIONS 7.1 Mycophenolic Acid When ENVARSUS XR is prescribed with a given dose of mycophenolic acid (MPA) product, exposure to MPA is higher with ENVARSUS XR coadministration than with cyclosporine coadministration because cyclosporine interrupts the enterohepatic recirculation of MPA while tacrolimus does not. Monitor for MPA associated adverse reactions and reduce the dose of concomitantly administered mycophenolic acid products as needed. 7.2 Effects of Other Drugs/Substances on ENVARSUS XR Table 4. Effects of Other Drugs/Substances on ENVARSUS XR a Drug/Substance Class or Name Drug Interaction Effect Recommendations Grapefruit or grapefruit juice b May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) Avoid grapefruit or grapefruit juice [see Warnings and Precautions (5.6 and 5.10)] Alcohol May modify the rate of tacrolimus release Avoid alcoholic beverages Strong CYP3A Inducers c such as: May decrease tacrolimus whole blood Increase ENVARSUS XR dose and Antimycobacterials (e.g., rifampin, trough concentrations and increase monitor tacrolimus whole blood trough rifabutin), anticonvulsants (e.g., the risk of rejection [see Warnings concentrations [see Dosage and phenytoin, carbamazepine and and Precautions (5.9)] Administration (2.3) and Clinical phenobarbital), St John s Wort Pharmacology (12.2)] Strong CYP3A Inhibitors c, such as: Protease inhibitors (e.g., nelfinavir, telaprevir, boceprevir, ritonavir), azole antifungals (e.g., voriconazole, posaconazole, itraconazole, ketoconazole), antibiotics (e.g., clarithromycin, troleandomycin, chloramphenicol), nefazodone Mild or Moderate CYP3A Inhibitors, such as: antibiotics (e.g., erythromycin), calcium channel blockers (e.g., verapamil, diltiazem, nifedipine, nicardipine), amiodarone, danazol, ethinyl estradiol, cimetidine, lansoprazole and omeprazole, azole antifungals (e.g., clotrimazole, fluconazole) Other drugs, such as: Magnesium and aluminum hydroxide antacids Metoclopramide Mild or Moderate CYP3A Inducers, such as: Methylprednisolone, prednisone May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6, 5.9 and 5.10)] May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6 and 5.10)] May increase tacrolimus whole blood trough concentrations and increase the risk of serious adverse reactions (e.g., neurotoxicity, QT prolongation) [see Warnings and Precautions (5.6 and 5.10)] May decrease tacrolimus concentrations Reduce ENVARSUS XR dose (for voriconazole and posaconazole, give onethird of the original dose) and adjust dose based on tacrolimus whole blood trough concentrations [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)] Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)] Monitor tacrolimus whole blood trough concentrations and reduce ENVARSUS XR dose if needed [see Dosage and Administration (2.3) and Clinical Pharmacology (12.2)] Monitor tacrolimus whole blood trough concentrations and adjust ENVARSUS XR dose if needed [see Dosage and Administration (2.3)] a ENVARSUS XR dosage adjustment recommendation based on observed effect of coadministered drug on tacrolimus exposures [see Clinical Pharmacology (12.2)], literature reports of altered tacrolimus exposures, or the other drug s known CYP3A inhibitor/inducer status b High dose or double strength grapefruit juice is a strong CYP3A inhibitor; low dose or single strength grapefruit juice is a moderate CYP3A inhibitor c Strong CYP3A inhibitor/inducer, based on reported effect on exposures to tacrolimus along with supporting in vitro CYP3A inhibitor/inducer data, or based on drug-drug interaction studies with midazolam (sensitive CYP3A probe substrate)